Chymase is known to be present in secretory granules of mast cells (MC), which are closely related to inflammation, as one type of inflammatory cell. Further, human chymase similarly is mainly present broadly in MCs in the skin, heart, vascular walls, intestines, and other tissue (Mast Cell Proteases in Immuunology and Biology; Caughey, G. H., ed; Marcel Dekker, Inc.: New York, 1995). Human MCs are known to increase with bronchial asthma, allergic dermatitis and other allergic diseases, arteriosclerosis (Kaartinen et al., Circulation, 1994, 90, 1669), myocardial infarction (Kovanen et al., Circulation, 1995, 92, 1084), and other circulatory system diseases and rheumatoid arthritis (Gotis-Graham et al., Arthritis Rheum., 1997, 40, 479). Further, it has been reported that the genetic polymorphism of chymase is correlated to the onset of eczema (Mao et al., Lancet, 1996, 348, 581). Human chymase produces angiotensin II (Ang II) specifically from angiotensin I (Ang I) in the same way as an angiotensin converting enzyme. Ang II is closely related to regulation of the blood pressure, diuretic regulation, the migration and proliferation of smooth muscle cells etc. in the cardiovascular system tissue, the growth of the extracellular matrix, and other hypertrophy and remodeling of the cardiovascular system (Hideki Okunishi; Naibunpitsu-Tonyobyoka, 1996, 3(6), 535). Human chymase is reported to have the following actions due to its protease activity in addition to. production of Ang II: 1) degradation of the extracellular matrix (Vartio et al., J. Biol. Chem., 1981,–256, 471), activation of collagenase (Kovanen et al., J. Biol. Chem., 1994, 269, 18134), and production of collagen (Kofford et al., J. Biol. Chem., 1997, 272, 7127); 2) causing release of inflammatory cytokine, for example, release of TGF β1 from extracellular matrix (Taipale et al., J. Biol. Chem., 1995, 270, 4689) and production of IL-1β (Mizutani et al., J. Exp. Med., 1991, 174, 821); and 3) activation of stem cell factor (SCF) causing differentiation and proliferation of MCs (Longley et al., Pro. Nat. Acad. Sci., 1997, 94, 9017). Further, rat MC chymase is known to cause degranulation of MCs through IgE receptors, release chemical mediators such as histamine, partially hydrolyze the apolipoproteins of low density lipoproteins (LDL) to make modified LDL incorporated into macrophages, and convert the macrophages to foam cells (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.: New York, 1995).
On the other hand, low molecular chymase inhibitors have already been shown in print (Protease Inhibitors; Barrett et. al., eds.; Elssevier Science B. V.: Amsterdam, 1986). Further, recently, as peptide inhibitors for human chymase, there have been α-keto acid derivatives (WO-A-93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738) and α,α-difluoro-β-keto acid derivatives (JP-A-9-124691), while as peptide-mimetic inhibitors, there are trifluoromethylketone derivatives (WO-A-96-33974, JP-A-10-53579), and α,α-difluoro-β-keto acid derivatives (JP-A-10-7661), while as nonpeptide inhibitors, there have been imidazolinedione derivatives (J. Med. Chem., 1997, 40, 2156), quinazoline derivatives (WO 97-11941), phenyl ester derivatives (JP-A-10-87567), etc. There are no examples however of commercialization as medicaments.
The above reports relating to chymase suggest that chymase plays an important role in the process of inflammation, repair, and cure of damaged tissue. That is, it breaks down the extracellular matrix at the inflammatory tissue, releases and activates inflammatory cytokine, causes cell migration and proliferation, reproduces the extracellular matrix, and makes the tissue repair. The excess reactions in this process are believed to be linked to various diseases. Therefore, by inhibiting chymase and suppressing the exacerbation of vascular permeability induced by chymase, utilization as a medicament for prevention and a medicament for treatment of allergic diseases such as bronchial asthma, cnidosis, atopic dermatitis, mastocytosis, scleriasis, rheumatic diseases such as arthritis, cardiac and circulatory system diseases arising due to abnormal exacerbation of Ang II production, for example, cardiac insufficiency, hypercardia, stasis cardiac diseases, hypertension, arteriosclerosis, peripheral circulatory disorders, revasoconstriction after PCTA, diabetic renal disorders or non-diabetic renal disorders, coronary: diseases including myocardial infarction, angioendothelia, or vascular disorders accompanying arterialization or atheroma may be given as examples.